Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. May 15, 2024; 16(5): 2060-2073
Published online May 15, 2024. doi: 10.4251/wjgo.v16.i5.2060
Epigenetic silencing schlafen-11 sensitizes esophageal cancer to ATM inhibitor
Jing Zhou, Mei-Ying Zhang, Ai-Ai Gao, Cheng Zhu, Tao He, James G Herman, Ming-Zhou Guo
Jing Zhou, Cheng Zhu, Ming-Zhou Guo, School of Medicine, NanKai University, Tianjin 300071, China
Jing Zhou, Mei-Ying Zhang, Ai-Ai Gao, Cheng Zhu, Ming-Zhou Guo, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
Tao He, Departments of Pathology, Characteristic Medical Center of The Chinese People’s Armed Police Force, Tianjin 300162, China
James G Herman, The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, United States
Ming-Zhou Guo, National Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing 100853, China
Author contributions: Zhou J performed the experiments, acquired, and analyzed data, and wrote the manuscript; Zhang MY, Gao AA, Zhu C, and He T provided critical feedback to the manuscript and performed chart review; Herman JG revised the manuscript for language polishing; Guo MZ conceive the study, revised the manuscript, and provided funding supporting.
Supported by the National Key Research and Development Program of China, No. 2018YFA0208902; National Science Foundation of China, No. 82272632, No. 81672318, and No. U1604281; Beijing Science Foundation of China, No. 7171008; and Youth Innovation Science Foundation of Chinese PLA General Hospital, No. 22QNCZ027.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of the Chinese PLA General Hospital (Approval No. 20090701-015).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Animal Ethics Committee of the Chinese PLA General Hospital (Approval No. 2022-X18-72).
Conflict-of-interest statement: The authors declare no potential conflict of interest.
Data sharing statement: Data that supports the findings of this study are available from the corresponding author upon reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ming-Zhou Guo, MD, PhD, Professor, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China. guomingzhou@301hospital.org
Received: November 30, 2023
Revised: February 26, 2024
Accepted: April 1, 2024
Published online: May 15, 2024
Processing time: 161 Days and 10.5 Hours
Abstract
BACKGROUND

Targeting DNA damage response (DDR) pathway is a cutting-edge strategy. It has been reported that Schlafen-11 (SLFN11) contributes to increase chemosensitivity by participating in DDR. However, the detailed mechanism is unclear.

AIM

To investigate the role of SLFN11 in DDR and the application of synthetic lethal in esophageal cancer with SLFN11 defects.

METHODS

To reach the purpose, eight esophageal squamous carcinoma cell lines, 142 esophageal dysplasia (ED) and 1007 primary esophageal squamous cell carcinoma (ESCC) samples and various techniques were utilized, including methylation-specific polymerase chain reaction, CRISPR/Cas9 technique, Western blot, colony formation assay, and xenograft mouse model.

RESULTS

Methylation of SLFN11 was exhibited in 9.15% of (13/142) ED and 25.62% of primary (258/1007) ESCC cases, and its expression was regulated by promoter region methylation. SLFN11 methylation was significantly associated with tumor differentiation and tumor size (both P < 0.05). However, no significant associations were observed between promoter region methylation and age, gender, smoking, alcohol consumption, TNM stage, or lymph node metastasis. Utilizing DNA damaged model induced by low dose cisplatin, SLFN11 was found to activate non-homologous end-joining and ATR/CHK1 signaling pathways, while inhibiting the ATM/CHK2 signaling pathway. Epigenetic silencing of SLFN11 was found to sensitize the ESCC cells to ATM inhibitor (AZD0156), both in vitro and in vivo.

CONCLUSION

SLFN11 is frequently methylated in human ESCC. Methylation of SLFN11 is sensitive marker of ATM inhibitor in ESCC.

Keywords: Schlafen-11; Esophageal squamous cell carcinoma; DNA methylation; Synthetic lethality; AZD0156

Core Tip: Targeting DNA damage repair (DDR) is a novel strategy for cancer therapy. Epigenetic-based synthetic lethality studies have been conducted recently. Schlafen-11 (SLFN11) has been reported to sensitize cancer cells by involving DDR. However, the detailed regulatory network in DDR remains controversial. This study explored the mechanism of SLFN11 in DDR, and further investigated the synthetic lethal efficiency of epigenetic silencing SLFN11 and ATM inhibitor. The results demonstrated that SLFN11 activated non-homologous end-joining and ATR/CHK1, while inhibiting the ATM/CHK2 signaling pathway. Epigenetic silencing SLFN11 sensitized esophageal cancer cells to ATM inhibitor both in vitro and in vivo.